Susceptibility to relapsing-progressive multiple sclerosis is associated with inheritance of genes linked to the variable region of the TcR beta locus: use of affected family-based controls.
We tested the hypothesis that susceptibility to relapsing-progressive (RP) (but not to relapsing-remitting [RR]) multiple sclerosis (MS) is associated with a gene linked to the TcR beta-chain variable region delimited by the Vbeta8-BamHI and Vbeta11-BamHI RFLP alleles in DRw15+ MS patients, using a contingency-table test of patient data and affected family-based controls. Control alleles and haplotypes were composed of parental marker alleles and haplotypes not transmitted to the affected child, in 90 simplex and 31 multiplex families from British Columbia. A total of 6,164 alleles at 11 loci were segregated through families of probands with RP MS or RR MS. The Vbeta8-Vbeta11 subhaplotype frequencies in the DRw15+ RP MS (but not RR MS) patients differed from control frequencies, because of an increase of the 2-1 subhaplotype (P=.02). Vbeta8-BamHI and Vbeta11-BamHI allele frequencies (P=.05 and .009, respectively) in the DRw15+ RP MS (but not RR MS) patients differed from control frequencies. The Vbeta1-Vbeta8 subhaplotype frequencies in the DRw15- RP MS (but not RR MS) patients differed from control frequencies (P=.03), with a significantly increased frequency of the 1-1 subhaplotype (P=.01; RR=7.1) in RP MS versus RR MS patients. Susceptibility to RP MS is associated both with a recessive inheritance of a gene linked to the 3' (Vbeta11) end of the 2-1 subhaplotype defined by the Vbeta8-BamHI and Vbeta11-BamHI alleles in DRw15+ patients and with a gene, located on the 1-1 subhaplotype, defined by the Vbeta1-TaqI and Vbeta8-MspI alleles of the TcR beta-chain complex in DRw15- patients.
Hockertz
M K
MK
Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada V6T 2B5.
Paty
D W
DW
Beall
S S
SS
D000328:Adult; D000483:Alleles; D004247:DNA / Q000097:blood; D015245:Deoxyribonuclease BamHI; D004198:Disease Susceptibility; D005190:Family; D005260:Female; D008040:Genetic Linkage; D014644:Genetic Variation; D006801:Humans; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D012008:Recurrence; D012016:Reference Values; D012307:Risk Factors
D016693:Receptors, Antigen, T-Cell, alpha-beta; D004247:DNA; D015245:Deoxyribonuclease BamHI